The present invention, according to a specific aspect thereof, relates to pharmaceutical, veterinary or dietary compositions and the use thereof for a method of treatment or prophylaxis of depressed or inadequate intracellular pyridoxal phosphate levels in a human or animal patient resulting from a condition, wherein the pyridoxine (PN)--intracellular pyridoxal phosphate (PLP) pathway is disturbed or insufficient. The invention can make use of new diagnostic methods and means for diagnosing such depressed or inadequate pyridoxal phosphate levels or disturbance in the pathway, more particularly for use in conjunction with the said treatment or prophylaxis. More particularly, according to one aspect, the invention relates to that genus of the aforegoing compositions and methods, where the said disturbance of the pathway is due to an inherent cellular defect, e.g. caused by genetic oxidase polymorphism or immaturity of cells, resulting in deficient oxidase activity. The condition can be aggravated by chemical substances which are vitamin B6 antagonistic. Such substances can be biogenic. They can be toxins, e.g. of microbal origin, or toxic substances to which the body was exposed accidentally, but the invention has particular application to counteracting side-effects of a variety of pharmaceuticals which are vitamin B6 antagonists and which may be used to combat diseases which lead to the aforesaid cellular defects.
The invention is particularly concerned with insufficiencies in the aforesaid pathway due to cellular immaturity causing depressed activity of oxidase enzymes.
The present invention, according to a specific aspect, relates to compositions for the treatment and prophylaxis of metabolic disturbances in infants, more particularly of elevated homocysteine and/or methionine levels in the blood of infants and pathological disturbances connected therewith.
The relationship between even moderately elevated blood homocysteine levels homocysteineaemia and various pathological conditions, in particular vascular and neurological diseases has been firmly established in adults. (Ueland et al, Scan. Clin. Lab. Invest. 1988, 48:215)
Hitherto, this problem was considered to primarily affect adults and possibly adolescents, since it was primarily believe to be connected with long term dietary factors, possibly enhanced by genetic factors.
It therefore came as a great surprise, when the present applicant conducted homocysteine measurements in the serum of new born and premature infants (something which had never before been reported) and discovered an amazing frequently of homocysteine abnormalities in such infants in addition to a number of important additional findings.
It was found that average homocysteine levels in healthy infants (6-7 .mu.mole/l) are much lower than in adults (for whom up to 16.3 .mu.mole/l is normal). However, surprisingly a relatively large proportion of infants were found to have relatively elevated homocysteine levels. Based on experiments conducted by the applicant on adults and various blood measurements carried out on the infants, it was possible to reach conclusions as to causes and potential consequences, and the present invention proposes appropriate countermeasures.
It was found that in ideal circumstances healthy infants, from healthy mothers and wholly breast fed are protected naturally against elevated homocysteine levels, a fact which indirectly confirms the danger residing in homocysteine. In healthy new-born infants plasma levels of pyridoxal, vitamin B12 and folate were found to be considerably higher than in adults. Applicant has established that these high levels provide a natural protective mechanism against accumulation of toxic homocysteine levels.
It was possible to correlate deficiencies in respect of one or more of the aforegoing with elevated homocysteine levels in the respective infants and detect connections with genetic factors, with pre-natal and post-natal maternal nutritional status (the latter being relevant to breast fed infants). However, most alarming of all was the discovery of the extent to which these elevated homocysteine levels can be ascribed to bottle feeding with non-human milk and milk formulae based on cow's milk. A careful assessment of certain differences between human and non-human milk has revealed plausible causes for the prevalence of homocysteineaemia amongst infants. In particular, cow's milk contains 4 times more methionine than mother's milk yet is lacking proportionally in factors which would prevent or counteract the transformation of this excessive amount of methionine into homocysteine.
Fraying and splitting of the vascular internal elastic membranes has been observed as a clinical symptom of elevated homocysteine levels in adults. This same symptom was described by Jaffe in 176 babies who had died of different causes during their first 3 months of life. Sudden infant death syndrome has been found to be particularly common amongst bottle-fed babies.
The vascular damage caused by homocysteine is well established. Research has shown that this kind of damage is the primary cause of and precondition for subsequent vascular damage by cholesterol. Research has further revealed that cholesterol only becomes dangerous once it has been oxidised to oxycholesterol, either in the diet or in vivo. This is brought about by the intervention of free radicals. In this context it is particularly alarming that homocysteine itself is a known stimulant for free radical induced oxidation of lipoproteins, including that of cholesterol-rich lipoproteins, this besides other harmful effects of free radicals in vivo. Moreover, in a manner to be explained further below, thermally processed bottle feed products are themselves rich in oxycholesterol but are deficient in counteracting substances present in human milk,
Even if the adverse factors described above, in particular elevated homocysteine result in no immediately apparent symptoms, they may predispose to atherosclerosis in later life.
The damage caused by homocysteine in infants is obviously not limited to the vascular system but may include many other tissues and systems including the central nervous system, which is particularly vulnerable at this stage.
The invention is inter alia based on the discovery of the above described hitherto unknown problem and seeks solutions to this and/or related problems.
The present invention is based on extensive research which has brought to light a large number of clinical or pathological conditions in animals or man associated with depressed or inadequate intracellular pyridoxal phosphate levels, resulting from factors whereby the pyridoxine-pyridoxal phosphate pathway is disturbed or rendered insufficient.